Axl Laurens Lukas Windah, Nanik Siti Aminah, Alfinda Novi Kristanti, Imam Siswanto, Muhammad Ikhlas Abdjan, Thae Thae Su Pyae Naing, Theint Su Wai, Yoshiaki Takaya, Yan Wang
The emergence of multidrug-resistant Plasmodium falciparum, particularly strains with multiple mutations in the dihydrofolate reductase enzyme (PfDHFR), necessitates novel inhibitors. This study employs a comprehensive computational approach to investigate dimeric resveratrols from the Shorea genus, a class of natural products with known bioactivity, as potential inhibitors of the highly resistant PfDHFR quadruple mutant. Density functional theory (DFT) was employed to optimize the geometry of 24 candidate compounds, followed by molecular docking to screen for binding affinity at the enzyme's active site. The most promising candidates were then subjected to extensive 250 ns molecular dynamics (MD) simulations to assess complex stability. Our screening identified (-)-ε-viniferin (1DR), maximol A (2DR), and hemsleyanol A (5DR) as top candidates from the docking results. MD simulations confirmed the stability of these complexes in the active site. Notably, hemsleyanol A (5DR) exhibited the strongest binding affinity (ΔGbind = -38.07 ± 0.05 kcal/mol), surpassing both the control pyrimethamine (-17.19 ± 0.04 kcal/mol) and the co-crystallized native ligand WR99210 (-31.46 ± 0.04 kcal/mol) calculated using the QM/MM-GBSA method. Furthermore, pharmacokinetic predictions revealed that hemsleyanol A possesses favorable drug-like properties. These findings establish hemsleyanol A as a potent lead compound against multidrug-resistant malaria. © The Author(s) 2026. This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International. https://creativecommons.org/licenses/by-nc-nd/4.0/.
Faculty of Science and Technology, Universitas Airlangga, Surabaya, 60115, Indonesia; Departement of Chemistry, Faculty of Science and Technology, Universitas Airlangga, East Java, Surabaya, 60115, Indonesia; Biotechnology of Tropical Medicinal Plants Research Group, Universitas Airlangga, East Java, Surabaya, 60115, Indonesia; Bioinformatic Laboratory, UCoE Research Center for Bio-Molecule Engineering, Universitas Airlangga, Surabaya, 60115, Indonesia; Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, University Engineering Research Center for Chemistry of Characteristic Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guangxi, Guilin, 541004, China; Department of Chemistry, Faculty of Mathematics and Natural Science, Universitas Negeri Surabaya, East Java, Surabaya, 60231, Indonesia; Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku, Aichi, Nagoya, 468-8503, Japan
